Chemotherapy in Advanced Nasopharyngeal Cancer

Chemotherapy in Advanced Nasopharyngeal Cancer

In contrast to many other cancers of the head and neck, patients with
nasopharyngeal carcinoma tend to be younger and have few, if any,
comorbidities. In other words, if cured of nasopharyngeal carcinoma,
these individuals live long and productive lives. Therefore, the
treatment of nasopharyngeal carcinoma, while challenging, can be
particularly rewarding for the oncologist.

For years, nasopharyngeal carcinoma was treated almost exclusively by
radiotherapy, but, in recent years, che-motherapy has assumed an
important role in its management, as detailed by Drs. Ali and
Al-Sarraf. However, not all patients with nasopharyngeal carcinoma
require chemotherapy. The question is: In which patients do the
benefits of chemotherapy outweigh its toxicity?

M1 Disease

Patients with systemic metastases are candidates for chemotherapy.
However, Drs. Ali and Al-Sarraf are perhaps too optimistic about the
number of these patients cured with present-day therapy, because, by
and large, systemic metastases still represent a death sentence.
Improved systemic therapy is clearly necessary, and every patient
with metastatic disease should be encouraged to enter a clinical trial.

In their article, Drs. Ali and Al-Sarraf consider patients with
metastatic disease and those with locally recurrent disease as
belonging to the same categoryan approach that may not be
appropriate in nasopharyngeal carcinoma. Some patients with locally
recurrent disease may indeed be cured by further therapy, but there
is no such thing as standard therapy in this population;
treatment requires a great deal of individualization and may include
brachytherapy, stereotactic radiotherapy, surgery, and/or chemotherapy.

Bulky Cervical Nodal Metastases

With contemporary radiotherapy, persistence or recurrence of cancer
in the neck has become uncommon in nasopharyngeal carcinoma,[1-3] yet
patients with advanced neck disease do remain at relatively high risk
for developing distant metastases.[4]

The prospective, randomized Intergroup study 0099[2] enrolled 147
assessable patients with nasopharyngeal carcinoma, almost all of whom
had stage IV (but M0) disease, and two-thirds of whom had N2 or N3
disease. Results showed a survival benefit from the addition of
concomitant and adjuvant chemotherapy. Notably, the site of
recurrence was distant only in 14 of 69 patients after
radiotherapy alone vs 7 of 78 patients after combined therapy.
Therefore, cisplatin (Platinol) and fluorouracil, as administered in
Intergroup study 0099, are clearly worthwhile for such patients.

Advanced Primary Tumors

Intergroup study 0099[2] began in 1989, with external-beam
radiotherapy in doses up to only 70 Gy. The failure rate at the
primary site was 33% without chemotherapyvery similar to the
29% reported by M. D. Anderson Cancer Center after similar doses of
external-beam radiotherapy alone.[3]

Improvements in technology notwithstanding, most radiation
oncologists still do not believe that doses greater than
approximately 70 Gy can be safely delivered to the nasopharynx by
external beam alone. This opinion stems from the risk of injury to
such critical structures as the optic chiasm, brainstem, and temporal
lobes of the brain.

However, during the 1990s, several reports from North America,[5-7]
Europe,[8] and Asia[9] were published, suggesting that doses
considerably higher than 70 Gy could be safely delivered to the
nasopharynx by adding brachytherapy. This strategy produced very high
rates of local control, exceeding 90%. Brachytherapy was delivered by
the permanent interstitial implantation of iodine-125,[6] the
temporary lowdose-rate intracavitary implantation of
cesium-137,[7] or the temporary highdose-rate intracavitary
implantation of iridium-192.[8,9] Each of these techniques appears to
be safe and effective, and, in the absence of controlled studies, the
choice is dictated by available expertise and resources.

In addition, Intergroup study 0099 showed a marked improvement in
local control when concomitant and adjuvant chemotherapy were added
to external-beam radiotherapy. Local only failures
occurred in 12 of 69 patients after radiotherapy vs 3 of 78 patients
after combined therapy. Local and other failures occurred
in 23 of 69 patients after radiotherapy vs 8 of 78 patients after
combined therapy. Thus, cisplatin and fluorouracil, as administered
in Intergroup study 0099, improved tumor control at the primary site,
albeit when added to what today would be regarded as a suboptimal
dose of radiotherapy.

Conclusions

Only further research will determine whether chemotherapy will
benefit or harm patients who receive external-beam radiotherapy plus
brachytherapy (or whether brachytherapy will benefit or harm those
who receive external-beam radiotherapy plus chemotherapy). In the
interim, it is reasonable to administer chemotherapy as per
Intergroup study 0099 to those with bulky nodal disease and, perhaps,
also to those with T4 primary cancer.